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Peer-reviewedCC BYCancers

O-GlcNAcylated TCF4 Drives Ferroptosis Resistance and Tumor-Associated Macrophage Infiltration to Promote Colorectal Cancer Liver Metastasis.

  • Han Yang1
  • Jinhao Yu2
  • Dong Hou2
  • Jiaxin Lin3
  • Guangyao Chen4
  • Bin Yang2
  • Dongming Lai2
  • Fanghai Han2,4
  • Hongming Li3
4 affiliations
  1. 1Department of Laboratory Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
  2. 2Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
  3. 3Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China.
  4. 4Department of Gastrointestinal Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
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Abstract

Background: Colorectal cancer liver metastasis (CRLM) remains a major cause of mortality in colorectal cancer (CRC), while the upstream molecular mechanisms linking tumor cell adaptation and immune microenvironment remodeling remain poorly understood. Methods: By integrating single-cell RNA sequencing, multi-omics analysis, clinical cohorts, and functional experiments, we investigated the role and mechanism of TCF4 post-translational modification in CRLM progression. Results: We identified O-GlcNAcylated TCF4 as a critical driver of CRLM. TCF4 was significantly upregulated in CRLM and associated with poor prognosis. Mechanistically, OGT-mediated O-GlcNAcylation at Ser163 promoted TCF4 nuclear localization and enhanced its transcriptional activity. O-GlcNAcylated TCF4 directly activated GPX4 transcription, conferring ferroptosis resistance and preserving the malignant characteristics of CRC cells. Furthermore, TCF4 promoted CSF1 secretion, activating the CSF1/CSF1R axis to facilitate TAM recruitment and M2 macrophage polarization, thereby establishing an immunosuppressive metastatic niche. Conclusions: Our study reveals an O-GlcNAcylated TCF4-ferroptosis-immune regulatory axis that coordinates tumor intrinsic adaptation and microenvironmental remodeling during CRLM progression, providing potential therapeutic targets for preventing CRLM.

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Cite

BibTeXRIS
BibTeX
@article{yang2026oglcnacylated,
  title = {{O-GlcNAcylated TCF4 Drives Ferroptosis Resistance and Tumor-Associated Macrophage Infiltration to Promote Colorectal Cancer Liver Metastasis.}},
  author = {Han Yang and Jinhao Yu and Dong Hou and Jiaxin Lin and Guangyao Chen and Bin Yang and Dongming Lai and Fanghai Han and Hongming Li},
  journal = {Cancers},
  year = {2026},
  month = sep,
  doi = {10.3390/cancers18193105},
  url = {https://europepmc.org/article/MED/42882800},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - O-GlcNAcylated TCF4 Drives Ferroptosis Resistance and Tumor-Associated Macrophage Infiltration to Promote Colorectal Cancer Liver Metastasis.
AU  - Han Yang
AU  - Jinhao Yu
AU  - Dong Hou
AU  - Jiaxin Lin
AU  - Guangyao Chen
AU  - Bin Yang
AU  - Dongming Lai
AU  - Fanghai Han
AU  - Hongming Li
PY  - 2026
DA  - 2026/09/24
JO  - Cancers
DO  - 10.3390/cancers18193105
UR  - https://europepmc.org/article/MED/42882800
AB  - Background: Colorectal cancer liver metastasis (CRLM) remains a major cause of mortality in colorectal cancer (CRC), while the upstream molecular mechanisms linking tumor cell adaptation and immune microenvironment remodeling remain poorly understood. Methods: By integrating single-cell RNA sequencing, multi-omics analysis, clinical cohorts, and functional experiments, we investigated the role and mechanism of TCF4 post-translational modification in CRLM progression. Results: We identified O-GlcNAcylated TCF4 as a critical driver of CRLM. TCF4 was significantly upregulated in CRLM and associated with poor prognosis. Mechanistically, OGT-mediated O-GlcNAcylation at Ser163 promoted TCF4 nuclear localization and enhanced its transcriptional activity. O-GlcNAcylated TCF4 directly activated GPX4 transcription, conferring ferroptosis resistance and preserving the malignant characteristics of CRC cells. Furthermore, TCF4 promoted CSF1 secretion, activating the CSF1/CSF1R axis to facilitate TAM recruitment and M2 macrophage polarization, thereby establishing an immunosuppressive metastatic niche. Conclusions: Our study reveals an O-GlcNAcylated TCF4-ferroptosis-immune regulatory axis that coordinates tumor intrinsic adaptation and microenvironmental remodeling during CRLM progression, providing potential therapeutic targets for preventing CRLM.
SN  - 2072-6694
ER  -